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Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

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Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

Andrés González et al. Pharmaceutics.

Abstract

Antibiotic resistance is a major cause of the increasing failures in the current eradication therapies against Helicobacter pylori. In this scenario, repurposing drugs could be a valuable strategy to fast-track novel antimicrobial agents. In the present study, we analyzed the inhibitory capability of 1,4-dihydropyridine (DHP) antihypertensive drugs on the essential function of the H. pylori response regulator HsrA and investigated both the in vitro antimicrobial activities and the in vivo efficacy of DHP treatments against H. pylori. Six different commercially available and highly prescribed DHP drugs-namely, Nifedipine, Nicardipine, Nisoldipine, Nimodipine, Nitrendipine, and Lercanidipine-noticeably inhibited the DNA binding activity of HsrA and exhibited potent bactericidal activities against both metronidazole- and clarithromycin-resistant strains of H. pylori, with minimal inhibitory concentration (MIC) values in the range of 4 to 32 mg/L. The dynamics of the decline in the bacterial counts at 2 × MIC appeared to be correlated with the lipophilicity of the drugs, suggesting different translocation efficiencies of DHPs across the bacterial membrane. Oral treatments with 100 mg/kg/day of marketed formulations of Nimodipine or Nitrendipine in combination with omeprazole significantly reduced the H. pylori gastric colonization in mice. The results presented here support a novel therapeutic solution for treatment of antibiotic-resistant H. pylori infections.

Keywords: Helicobacter pylori; HsrA; dihydropyridines; repurposing.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
In vitro inhibition of HsrA DNA binding activity by selected DHP drugs. (a) Electrophoretic mobility shift assays (EMSAs) showing the ability of recombinant HsrA to specifically bind the promoter region of target porGDAB operon. Increasing concentrations of HsrA (indicated in μM) were mixed with 120 ng of target promoter and separated on a 6% PAGE. The Anabaena gene pkn22 was included as non-specific competitor DNA in all assays. (b) DNA fragments were mixed with 6 μM of recombinant HsrA protein in the presence of 2, 1, 0.5 and 0.1 mM of DHPs.
Figure 2
Figure 2
Local overviews of the best ranked docking poses of Nifedipine (a), Nicardipine (b), Nisoldipine (c), Nimodipine (d), Nitrendipine (e) and Lercanidipine (f) interaction with HsrA. Ribbon model and transparent molecular surface showing the interacting residues of HsrA to each DHP. The helix-turn-helix (HTH) DNA binding motif of HsrA is highlighted in blue. Some interacting residues are indicated.
Figure 3
Figure 3
Time–kill kinetics of DHP drugs against H. pylori strain ATCC 700684. Bacterial counts were determined at time zero and after 4, 8, and 24 h of incubation with two times the MIC. Mixtures of bacteria with DMSO (vehicle) instead of DHP were used as controls. Values are the averages of six independent determinations; vertical bars represent standard deviations. Please note that in some instances, the error bar is smaller than the symbols used.
Figure 4
Figure 4
Antimicrobial effects of Nimodipine and Nitrendipine against H. pylori stomach colonization in mice. (a) Bacterial counts from gastric biopsies are presented as CFU of H. pylori per mg of stomach. (b) Quantitative PCR from gastric biopsies are presented as a ratio of bacteria per 10,000 murine cells. Hp, H. pylori strain pre-mouse Sydney Strain 1 (PMSS1). Om, omeprazole. Hp + Om, infected non-treated mice (n = 10), Hp + Nimodipine + Om (n = 9) and Hp + Nitendipine + Om (n = 9). Graphic representations are box plots, with the box representing 50% of values around the median (horizontal line) and the whiskers representing the minimum and maximum of all the data. * p < 0.05, ** p < 0.01 H. pylori-infected non-treated mice versus H. pylori-infected treated mice.

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